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Conditions

Cryopyrin-associated periodic syndrome and related inflammasomopathies

Cryopyrin-associated periodic syndrome and related inflammasomopathies are rare genetic conditions characterised by recurrent inflammatory episodes that are triggered by exposure to cold temperatures.

Overview

Cryopyrin-associated periodic syndrome (CAPS) and related inflammasomopathies are a group of rare genetic, cold-triggered autoinflammatory conditions that occur as a result of anomalies in inflammasomes. They include diseases caused by pathogenic genetic variants in NLRP3, NLRP12, NLRC4 and NLRP1. These genes code for members of the NLR (NOD-like receptor) protein family, which can form or regulate inflammasomes (intracellular protein complexes that activate inflammatory responses). Typical features include episodic fevers, joint pain and skin rash, and are triggered by exposure to cold temperatures.

Clinical features

Inflammasomopathies are diseases in which the key feature is inflammasome overactivity. The inflammasome is a cellular structure that senses danger signals reflective of pathogen or endogenous tissue damage. During activation, inflammatory cytokines are released, particularly interleukin-1 (IL-1).

CAPS conditions

CAPS has three distinct autoinflammatory phenotypic conditions, all caused by disrupted NLRP3 inflammasome activity. Patients may have overlapping features from the different subtypes, and although originally described as three separate conditions, they are now thought of as a continuous spectrum of disease.

  1. Familial cold autoinflammatory syndrome (FCAS): This is the mildest cryopyrinopathy, presenting with disease flares triggered by cold exposure. Symptoms include:
    • fever, usually resolving within 72 hours;
    • urticarial rash;
    • conjunctival injection;
    • arthralgia; and
    • leukocytosis during flares.
  2. Muckle-Wells syndrome: This has similar symptoms with more frequent disease flares, which may or may not be cold-induced. Additional symptoms may also include:
    • progressive sensorineural hearing loss; and
    • secondary (AA) amyloidosis affecting the kidneys, heart and gastrointestinal tract.
  3. Neonatal-onset multisystem inflammatory disease (NOMID): This is the most severe CAPS, presenting shortly after birth with life-threatening complications. Clinical features include:
    • persistent, migratory, urticarial-like rash;
    • near-continuous fever;
    • distinctive facial features, such as frontal bossing and a saddle-shaped nose;
    • sensorineural hearing loss;
    • chronic aseptic meningitis;
    • cerebral atrophy;
    • uveitis;
    • cartilaginous proliferation with epiphyseal overgrowth;
    • hepatosplenomegaly with widespread lymphadenopathy; and
    • failure to thrive.

Related inflammasomopathies

NLRP12-associated autoinflammatory disease presents similarly to other inflammasomopathies with episodic disease flares, often triggered by cold exposure. This is also termed as familial cold-induced autoinflammatory syndrome 2 (FCAS2).

Clinical features are often variable and can include:

  • fever lasting up to two weeks;
  • pruritic urticarial rash;
  • arthralgia and myalgia;
  • oral and genital ulcers;
  • diarrhoea with abdominal pain; and
  • lymphadenopathy

NLRC4-associated autoinflammatory disease, also known as autoinflammation with infantile enterocolitis (AIFEC), leads to a broad spectrum of clinical features with severe, neonatal-onset disease at its most severe.

Clinical features include:

  • episodic fevers;
  • urticarial rash;
  • neonatal enterocolitis, which can be life-threatening; and
  • haemophagocytic lymphohistiocytosis (HLH), which can occur in the neonatal period in the most severe forms of the condition (though risk of HLH remains into adulthood).

NLRP1-associated disease causes autoinflammation with arthritis and dyskeratosis, with cutaneous features being prominent. These include:

  • keratoderma (thickened skin, mainly affecting the hands and soles of the feet);
  • multiple palmoplantar benign skin tumours;
  • keratosis lichenoides chronica (a chronic thickened purple rash);
  • recurrent fevers;
  • arthralgia;
  • corneal erosions; and
  • corneal dyskeratosis.

Genomics

Inflammasomopathies are caused by pathogenic variants in genes that form or interact with inflammasome structures (see table 1). All of these conditions are caused by monoallelic pathogenic variants, causing a gain-of-function effect in the resulting protein. This leads to excessive inflammasome activity, with overproduction of pro-inflammatory cytokines.

NLRP3 codes for cryopyrin, an intracellular protein sensor that co-ordinates assembly of the inflammasome following detection of pathogen-associated and endogenous triggers.

Across all three CAPS conditions, pathogenic variants are typically single nucleotide missense variants in exon 3 affecting the NACHT domain of NLRP3. Severe phenotypes (such as NOMID) may be caused by specific amino acid changes that severely disrupt the cryopyrin protein. Examples of these NLRP3 variants include p.Y570C, p.F309S and p.F523L.

Somatic mosaicism has been described in association with CAPS, and appears to be particularly prevalent in severe phenotypes such as NOMID. Some genetic variants have also been associated with different subtypes – for example, p.R260W and p.D303N have been associated with Muckle-Wells syndrome and NOMID in different individuals.

FCAS is the mildest and most common CAPS subtype. A founder variant (NLRP3 p.L353P) is frequently found in North America, accounting for up to 75% of affected individuals.

Table 1: Genes that cause inflammasomopathies

Gene Mode of inheritance Penetrance Condition Protein
NLRP3 Autosomal dominant* Variable CAPS, including FCAS, Muckle-Wells syndrome and NOMID Cryopyrin
NLRP12 Autosomal dominant Variable Familial cold-induced autoinflammatory syndrome 2 Monarch 1
NLRC4 Autosomal dominant Complete Autoinflammation with infantile enterocolitis (AIFEC) NLR family CARD domain-containing protein 4
NLRP1 Autosomal dominant and autosomal recessive Variable Autoinflammation with arthritis and dyskeratosis NLR family pyrin domain-containing protein 1

* NLRP3 variants can also be acquired somatically.

The Infevers registry has a curated database of genetic variants that have been associated with hereditary autoinflammatory conditions.

Diagnosis

Definitive diagnoses of inflammasomopathies should include a genetic diagnosis. Typically, this will test constitutional (germline) DNA via a blood sample. Where the clinical features suggest a somatic variant (such as no prior family history and/or presentation in adulthood), haematopoietic/skin tissue should be sampled.

The most recent European Alliance of Associations for Rheumatology (EULAR) diagnostic guidelines for CAPS outline the need for:

  • episodic flares of systemic inflammation;
  • elevated inflammatory markers: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR); and
  • preferably, genomic testing using massively parallel sequencing (sometimes called next-generation sequencing), with deep sequencing required to detect some somatic variants.

In CAPS, the condition may become apparent in the first few months of life, particularly in the NOMID subtype. However, due to the wide clinical spectrum described and the occurrence of somatic variants, the conditions may also initially present in adults.

NLRP12-associated disease may be distinguished from CAPS by the presence of oral and/or genital ulcers with longer episodic flares of systemic inflammation.

NLRC4-associated disease may be distinguished from other inflammasomopathies with clinical features such as early enterocolitis and features of haemophagocytic lymphohistiocytosis. In addition, very high levels of serum IL-18 levels may be found (>100-fold above normal healthy controls).

NLRP1-associated disease may be distinguished by increased skin-related manifestations alongside episodic flares of systemic inflammation. Patients may also show elevated IL-18 levels.

For information about testing, see ‘Child with a suspected autoinflammatory condition‘.

CAPS and related inflammasomopathies may be identified before any symptoms appear; for example, through the Generation Study. Confirmation of the diagnosis will require referral to autoinflammatory or specialist rheumatology services. Please refer to the local pathway for your region for this condition.

Inheritance and genetic counselling

The inflammasomopathies are most frequently autosomal dominant conditions caused by heterozygous (monoallelic) pathogenic genetic variants. Mild forms of CAPS have a prevalence of 1 in 1,000,000 people, while the other inflammasomopathies discussed here are very rare, with less than 50 cases described in the literature.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. Note that de novo variants may also arise, and that somatic variants should be considered in these cases.

Incomplete penetrance (where not everyone who has the variant develops the disease) is described in NLRP3-, NLRP12– and NLRP1-associated disease.

  • Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
  • The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).

Autosomal recessive inheritance has been described in some patients with NLRP1-associated autoinflammation with homozygous missense pathogenic variants. Presenting features have included autoinflammation with arthritis and dyskeratosis, and juvenile recurrent respiratory papillomatosis.

  • If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
    • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
    • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
    • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

Somatic variants have also been described in association with CAPS (NLRP3-related disease). This may be suspected in patients presenting with atypical features or in adult-onset disease, or those without family history of autoinflammation. Somatic variants are changes to DNA in body cells that happen after conception. They are not inherited from a parent and may only be transmitted from an affected individual to their offspring if present in the egg or sperm cells (this is termed germline mosaicism).

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Management

Inflammasomopathies are rare, complex conditions and are best managed by a multidisciplinary autoinflammatory and/or specialist rheumatology service. Treatment is aimed at controlling inflammation and preventing life-threatening complications such as amyloidosis.

For CAPS, anti-IL-1 treatments are used in patients with a definitive diagnosis over five years old. Specialist commissioning guidance in the UK is available for the treatment of CAPS. Treatment includes:

  • canakinumab: an anti-IL-1β monoclonal antibody;
  • anakinra: recombinant IL-1 receptor antagonist; and
  • rilonacept: an IL-1 fusion protein that binds IL-1.

Other inflammasomopathies may also be treated with anti-IL-1 agents. However, in some NLRC4-associated autoinflammation, anti-IL-18 inhibition may also be required. Patients with HLH may require interferon-gamma antagonists, or haematopoietic stem cell transplantation (HSCT) may be required for life-threatening cases.

Mild or intermittent inflammatory symptoms may be treated with steroid-sparing agents, such as non-steroidal anti-inflammatory agents or corticosteroids.

CAPS and related inflammasomopathies may be identified before any symptoms appear; for example, through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 08/11/2025
  • Next review due: 08/11/2027
  • Authors: Dr Jesmeen Maimaris
  • Reviewers: Dr Eleanor Hay